1. Field of Invention
The present inventive subject matter relates to novel foamable delivery systems. The present inventive subject matter further relates to pharmaceutical compositions and methods for treating a disease, disorder, or condition using the inventive delivery systems. The present inventive subject matter further relates to methods for making and methods for delivering a foamable pharmaceutical composition. While these foamable drug delivery systems may be utilized for administration of a wide variety of drugs to epithelial tissues to treat a wide variety of diseases, disorders, or conditions, the inventive foamable drug delivery systems are particularly useful for treating diseases affecting mammalian skin and mucous membranes by application or instillation of a pharmaceutically active agent that can modify the appearance, metabolic or functional state, permeability, and/or health of a living organism.
2. Background
Foamable dosage forms are known in the art generally as suitable for topical application to mammals. However, foams are further known as a volatile dosage form that do not exhibit a great deal of stability.
Foam Stability
Foams are thermodynamically unstable systems. Since the total surface area in a foam is large, there is a considerable amount of surface energy present. Accordingly, a surface active agent is necessary to achieve any reasonable degree of stability so the foam can last for a reasonable amount of time.
Good emulsifying agents are, in general, also good foaming agents, since the factors influencing emulsion stability against droplet coalescence and foam stability against bubble collapse are similar. The stability of a foam depends upon three principal factors: (1) the tendency for liquid films to drain and become thinner; (2) the tendency of foam bubbles to rupture as a result of random disturbances; and (3) change in bubble size. Other factors which may significantly influence foam stability include evaporation and gas diffusion through the liquid films.
Foam Drainage
Initially, foam drainage takes place mainly by gravitational flow, allowing the spheres of gas in the foam to become closer together. Foaming agents play an important role at this stage in restricting gravitational flow to a level where local disturbances and consequent film rupture is minimized.
When the films between the gas spheres have attained a thickness on the order of micrometers, gravitational flow becomes extremely slow. When the bubble wall becomes sufficiently thin to be permeable, the gas in the smaller bubbles diffuses into adjacent bubbles to equalize the pressure and produce larger bubbles. This spontaneous process increases the average bubble size without film rupture. The predominant drainage mechanism then involves liquid being discharged locally via capillary action at positions of interfilm contact known as Plateau borders, where the liquid capacity is relatively high, existing throughout the foam. The final, stable equilibrium product is a fragile, honeycomb structure, in which the separating films have plane surfaces.
Foam drainage causes the liquid films separating the gas bubbles to become thinner. This usually leads to film rupture.
Film Rupture
In addition to film drainage, the stability of a film depends on the ability of the liquid film to resist excessive local thinning and rupture occurring as a result of random disturbances. A number of factors may be involved with varying degrees of importance, depending on the nature of the particular foam in question.
For example, when a film is subjected to local stretching as a result of some external disturbance, the consequent increase in surface area will be accompanied by a decrease in the surface excess concentration of foaming agent and a resulting local increase in surface tension. A certain time is required for surfactant molecules to diffuse to this surface region and restore the original surface tension. This increased surface tension may persist for long enough to cause the disturbed film region to recover its original thickness, stabilizing the foam.
The stress that creates regions of higher surface tension is always present in a foam film. The liquid film is flat at one place and curved convexly at another, where the liquid accumulates in the interstices between the bubbles. The convex curvature creates a capillary force, called the Laplace effect, that sucks liquid out of connected foam films so that internal liquid flows constantly from the flatter to the more curved parts of the films. As the liquid flows, the films are stretched, new surfaces of higher tension are created, and a counter-flow across the surfaces is generated to restore the thinned-out parts of the films, a process called the Marangoni effect. In this way, the foam films are in a constant state of flow and counterflow, one effect creating the conditions for its reversal by the other.
Rupture of the liquid films separating the bubbles leads to coalescence of the bubbles and complete collapse of the foam structure.
Changes in Bubble Size
Change in bubble size can lead to thinning of the lamellae and may cause mechanical shocks that result in film rupture. As a foam ages, the small bubbles become smaller and the large bubbles grow larger. This occurs because the pressure in a small bubble is higher than that in large bubbles. The difference in pressure between the two bubbles increases until the smaller bubble disappears completely. The resulting rearrangement of the bubbles in the foam could lead to an increased possibility of mechanical shock followed by film rupture and coalescence.
Surface Rheology
Rheology is the science of deformation and flow of matter. The mechanical properties of the surface films of a foam have a considerable influence on foam stability. First, high bulk liquid viscosity retards the rate of foam collapse. However, high surface viscosity also produces strong retardation of bulk liquid flow close to the surfaces and, consequently, the drainage of thick films is considerably more rapid than that of thin films, which facilitates the attainment of a uniform film thickness. Second, surface elasticity facilitates the maintenance of a uniform film thickness. However, the existence of rigid, condensed surface films is detrimental to foam stability, owing to the very small changes in area over which such films show elasticity.
A number of U.S. patents have previously been granted disclosing the use of foams and mousses as pharmaceutical or cosmetic compositions, as drug delivery systems, and for skin care. The majority of these patents pertain to specific formulations containing specific drugs for treating specific disorders. Representative of this body of art are the following U.S. patents.
Dole et al., U.S. Pat. No. 4,847,068, disclose a skin care composition in the form of an aerosol mousse comprising mineral oil, an emulsifier, water, and a propellant.
Schmidt et al., U.S. Pat. No. 5,002,680, disclose a skin cleansing aerosol mousse-forming emulsion comprising a concentrate, a mild non-soap anionic or amphoteric surfactant, a polymeric skin feel aid, a moisturizer which is preferably glycerin, water, and a propellant.
Lins, U.S. Pat. No. 5,167,950, discloses a high alcohol content aerosol antimicrobial mousse comprising a hydrocarbon propellant, ethanol or isopropyl alcohol, a water-dispersible polymeric gelling agent, an amphiphilic system consisting of at least one alcohol with a hydrocarbon group of from 16 to 22 carbons, and at least one nonionic surfactant.
Seki et al., U.S. Pat. No. 5,397,564, disclose an aerosol sherbet-like foam preparation for topical use, primarily for skin cooling, comprising water, a lower alcohol, liquefied petroleum gases, and dimethyl ether.
Lisboa et al., U.S. Pat. No. 5,679,324, disclose a low stinging and low burning aerosol foamable fragrance composition which forms a fast breaking foam containing a surfactant, a propellant, a fragrance, a thickener, and a cosmetic vehicle.
Vinski et al., U.S. Pat. No. 6,030,931, disclose a foaming cleansing composition free of water insoluble emollients containing an anionic surfactant and an amphoteric surfactant, packaged in a non-aerosol dispenser.
Osborne, U.S. Pat. No. 6,060,085, discloses a semisolid aqueous gel pharmaceutical composition customized for treatment of acne and herpes lesions. The composition includes a dissolved pharmaceutical that has the capacity to permeate the stratum corneum layer of the epidermis and become available systemically, and a pharmaceutical in a micro-particulate state that does not readily cross the stratum corneum of the epidermis.
Jones et al., U.S. Pat. No. 6,126,920, disclose a method of treating a skin disease with a foamable corticosteroid-containing pharmaceutical composition comprising a corticosteroid active substance; a quick-break foaming agent comprising an aliphatic alcohol, a fatty alcohol, water, and a surface active agent; a propellant; and a buffering agent.
Mohammadi, U.S. Pat. No. 6,264,964, discloses a foaming cosmetic product comprising a container with a nozzle outlet and a foaming mechanism, a crosslinked non-emulsifying polysiloxane elastomer, and a carboxyvinyl polymer.
Each of these patented formulations exhibits certain disadvantages and/or deficiencies. Accordingly, there remains a need in the art for improved formulations containing an active therapeutic agent that more effectively target epithelial cell tissue for the treatment of diseases, disorders, and conditions thereof. The present inventive subject matter addresses this need by providing, at a minimum, one of the following improvements: improved delivery of active therapeutic agent(s), decreased inconvenience and irritation, increased ease of use for the patient, and reduced degradation of the active therapeutic agent(s). Further, the present inventive subject matter may beneficially affect the appearance, metabolic or functional state, or permeability of a tissue or living organism, resulting in improvements in the health of the living organism at the expense of an antagonist thereto, such as pathogenic organisms and other disease states involving cells.